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Biomedical subjects

K Macleod

Publications and source records attributed to K Macleod.

14 recordsLinked to original sources
PubMed2004

Perioperative lower limb venous haemodynamics in patients under general anaesthesia.

BACKGROUND: This study prospectively determined the haemodynamic changes in the lower limb venous circulation during and shortly after elective abdominal surgery, performed under general anaesthesia. METHODS: Ten females, aged 36-65 yr, ASA I or II, undergoing total abdominal hysterectomy had their peak, mean and minimum velocities, diameter, volume flow and venous pulsatility (peak-minimum/mean velocity) measured in the left popliteal vein on recumbency with duplex at: (i) baseline, (ii) 15 min after induction, (iii) during surgery, and (iv) in recovery 30 min after extubation. Anaesthesia was induced with fentanyl and propofol, paralysis with vecuronium, maintenance with isoflurane in nitrous oxide 66%, and analgesia with morphine. Results are presented as percentage difference from baseline mean value. The Friedman and Wilcoxon([corrected(*)]) tests were applied. RESULTS: Mean velocity decreased by 23.6% during surgery and by 34.6% in recovery (P<0.05(*)). Minimum velocity was decreased by 56% during surgery and by 78% in recovery (P<0.05). The volume flow decreased by 26% during surgery, and by 54.4% in recovery (P<0.001). Diameter and peak velocity changed little at surgery and recovery (P>0.2). In contrast, the pulsatility increased by 30% on induction, 83% on surgery and 109% in recovery (P<0.05). Compared with baseline, haemodynamic changes on induction were small (P>0.1(*)). CONCLUSIONS: A significant decrease in the volume flow, mean and minimum velocities was noted during and immediately after elective total abdominal hysterectomy under general anaesthesia in ASA I and II patients. Flow changes in early recovery mirrored or enhanced those noted intraoperatively. Despite venous flow attenuation, haemodynamic readjustments produced a significant and progressive enhancement of venous flow pulsatility during the course of the procedure.

Adult↗
PubMed2000

Tumor suppressor genes.

Although tumor suppressor genes continue to be discovered, the most recent advances have been made in attributing new and exciting functions to existing ones - such as the apparent role of VHL as a regulator of proteolysis. Great insights have also come from piecing genes together into pathways and networks. For instance the discovery that cyclin D1 is regulated by beta-catenin/Tcf-4 allows us to tie the APC pathway to the RB pathway and cell cycle control. Similarly, tumor suppressor genes have been fitted together with oncogenes into the various pathways that regulate apoptosis such that tumor suppressor function is now attributed to some of the basic components of the apoptotic machinery, such as caspases and Apaf-1. The great pace at which mouse models of tumorigenesis continue to advance our knowledge of tumor suppressor gene function has led us to look anew at the role of genes such as TCF-1 and SMAD-3 in human cancer. Finally, the realisation that different growth regulatory pathways give rise to generic signals suggests that future work may lie in integrating the signals from different pathways and in understanding the importance of protein levels to cellular function.

Animals↗
PubMed1999

pRb and E2f-1 in mouse development and tumorigenesis.

Our understanding of how RB and E2F-1 function has progressed significantly from the model in which RB negatively regulates expression of genes required for S phase by binding to and inhibiting E2F-1. Both RB and E2F-1 have been shown recently to possess additional properties and mechanisms of regulation relevant to developmental and tumorigenic processes. In particular, it is now realised that RB has E2F-independent tumor suppressor functions which rely upon the ability of RB to induce differentiation. For its part, E2F-1 is unique amongst E2F family members in its capacity to induce apoptosis and this function is clearly relevant to our appreciation of E2F-1 as a conditional tumor suppressor. E2F-1 can induce both apoptosis and S-phase transition and whether E2F-1 acts as an oncogene or a tumor-suppressor gene may depend on the extent to which E2F-1 induces apoptosis as opposed to G1/S transition.

Animals↗
PubMed1999

The development of Graves' disease and the CTLA-4 gene on chromosome 2q33.

Case-control studies suggest that the CTLA-4 gene may be a susceptibility locus for Graves' disease. The previously reported A/G polymorphism at position 49 in exon 1 of the CTLA-4 gene was, therefore, investigated in a case-control (n = 743) and family-based (n = 179) dataset of white Caucasian subjects with Graves' disease. The relationship between CTLA-4 genotype and severity of thyroid dysfunction at diagnosis was also investigated. An increase in frequency of the G (alanine) allele was seen in Graves' patients compared with control subjects (42% vs. 31.5%, respectively; corrected P<0.0002; odds ratio = 1.58), and a significant difference in the distribution of GG, GA, and AA genotypes was observed between the groups (chi2 = 21.7; corrected P<0.00003). Increased transmission of the G allele was seen from heterozygous parents to affected offspring compared to unaffected offspring (chi2 = 5.7; P = 0.025). Circulating free T4 concentrations at diagnosis were significantly associated with CTLA-4 genotype (F = 3.26; P = 0.04). These results support the hypothesis that CTLA-4 may play a role in regulating self-tolerance by the immune system and in the pathogenesis of autoimmune disorders such as Graves' disease.

Abatacept↗
PubMed1996

Developing a condition-specific measure of health for patients with dyspepsia and ulcer-related symptoms.

A patient-administered instrument for dyspepsia and symptoms suggestive of duodenal or gastric ulcer, based on the type of questions asked when taking a patient's history, was developed and tested using the following steps: literature reviews, devising the questions, testing the responses to the questions using factor analysis and internal consistency, assessing test-retest reliability, and validating the questionnaire by comparing patient responses to the SF-36 health survey questionnaire. The main sample consisted of 135 patients referred to an outpatient clinic with dyspepsia, and 152 patients in general practice who were not referred to a specialist. The final instrument produced a Cronbach's alpha of 0.72 and an intraclass correlation coefficient of 0.69. Patient scores on the dyspepsia questionnaire had small to moderate correlations with the SF-36 health survey, the largest correlation being with the SF-36 scale of pain. Patient scores were significantly related to general practitioner perceptions of symptom severity, family history of gastric ulcer disease, and whether the patient was referred. The questions asked in taking a clinical history from a patient with dyspepsia and other symptoms suggestive of ulcer disease can be used to construct a valid and reliable measure of the effect of dyspepsia on health.

Adult↗
PubMed1995

Safety and immunogenicity of a cold-adapted influenza A (H1N1) reassortant virus vaccine administered to infants less than six months of age.

A safe and effective influenza vaccine is needed to prevent serious influenza illness in infants younger than 6 months of age. The purpose of this study was to determine whether two doses of the cold-adapted (ca) influenza A reassortant vaccine would be safe and immunogenic in this age group. In the first part of this study, infants received two doses of 10(5) or 10(6) 50% tissue culture-infectious dose (TCID50) of the ca influenza vaccine separately from routine immunizations. In the second part of this study two 10(6) TCID50 doses of the ca influenza vaccine were given with routine immunizations at 2 and 4 or 2 and 6 months of age. The ca influenza vaccine was well-tolerated by participants in both parts of this study. Two doses of the ca influenza vaccine were immunogenic in infants who received them separately from routine immunizations; 83% of vaccinees developed protective titers of serum hemagglutination-inhibition (HAI) antibody. In contrast, when the ca vaccine was administered with routine immunizations, protective HAI antibody titers were induced in only 20% of those immunized at 2 and 4 months of age and 50% of those immunized at 2 and 6 months of age. There were no statistically significant associations between HAI antibody response to ca influenza vaccination and dose schedule, presence of passively acquired maternal HAI antibody, ethnic group or breast-feeding status. Young age at the time of first immunization, however, appeared to correlate with decreased response to the hemagglutinin antigen of the influenza A virus.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1995

The influence of vascular pressure and different primes on the fluid balance of, and oxygen supply to, the patient during CABG.

Detrimental changes of blood and erythrocyte rheology, and fluid exchange between the vascular and interstitial spaces, which influence the rate that oxygen is supplied to the patient, occur during cardiac bypass surgery. Venous flow is subject to a pulsatile and uncertain variation, because the vena cava is more than 30 mmHg below atmospheric pressure. This occurs because the patient is about 1 m above the air-blood surface of the bypass reservoir. Before any reliable study of fluid exchange can be undertaken this effect must be controlled. It was then established that optimum oxygen exchange occurs when equilibration of the plasma oncotic pressure and the capillary hydrostatic pressure is achieved without alteration of the interstitial fluid volume. At the lower arterial blood pressures used during bypass, it is necessary to reduce the plasma oncotic pressure by using an appropriate volume of crystalloid prime.

Coronary Artery Bypass↗
PubMed1994

Hyperthermia induces doxorubicin release from long-circulating liposomes and enhances their anti-tumor efficacy.

PURPOSE: To examine the possibility that hyperthermia would accelerate drug release from long-circulating liposomes, and enhance their antitumor activity. METHODS AND MATERIALS: Liposomes were prepared by thin film hydration technique. Hyperthermia was induced by ultrasound apparatus and a water bath heating system. The antitumor efficacy of treatment against RIF-1 tumor in C3H mice was evaluated by the tumor growth delay assay. RESULTS: In vitro drug release experiments demonstrated that increase in temperature from 37 degrees C to 41 degrees C resulted in about a sixfold increase in doxorubicin (DOX) release in a 1-h period. Increasing the temperature to 43 degrees C, resulted in only a modest additional drug release. Drug uptake studies showed that local hyperthermic treatment immediately following the drug administration dramatically enhanced Stealth liposome-encapsulated doxorubicin (S-DOX) uptake by tumors, but did not do so for free DOX. At 42 degrees C and at a dose of 10 mg/kg, the accumulation of S-DOX was about 10-fold and 2.5-fold higher than that with free drug and S-DOX at 37 degrees C, respectively. The antitumor efficacy study confirmed our hypothesis that the addition of hyperthermia to the treatment of RIF-1 tumors with doxorubicin encapsulated in long-circulating liposomes would enhance antitumor effects. Two hyperthermia treatments given at 24-h intervals appeared to be the most promising method of combining heat and long-circulating liposomes. The increased antitumor activity was not accompanied by increased toxicity, as determined by the body weight of the mice. CONCLUSION: Local hyperthermic treatment is able to accelerate DOX release from long-circulating liposomes, increase tumor uptake, and enhance their antitumor efficacy. The combination of local hyperthermia and long-circulating liposomes appears to show considerable promise in the treatment of localized diseases.

Animals↗
PubMed1992

The ets gene family.

Ets proteins have a conserved DNA-binding domain and regulate transcriptional initiation from a variety of cellular and viral gene promoter and enhancer elements. Some members of the Ets family, Ets-1 and Ets-2, cooperate in transcription with the AP-1 transcription factor, the product of the proto-oncogene families, fos and jun, while others, Elk-1 and SAP-1, form ternary complexes with the serum response factor (SRF). Certain ets gene family members possess transforming activity while others are activated by proviral integration in erythroleukaemias.

Amino Acid Sequence↗
PubMed1991

Derepression of mouse beta-major-globin gene transcription during erythroid differentiation.

Functional analysis of the mouse beta-major-globin gene promoter has revealed a negative regulatory element (-100 to -250 bp) which represses promoter activity in mouse erythroleukemia (MEL) cells. Promoter activity is induced 14-fold during terminal differentiation of MEL cells. Three major in vitro binding sites for NF1 (-250 bp), GATA-1 (-212 bp), and a sequence at -165 bp (BB1) have been defined in this region. Site-directed mutagenesis of any one of the three sites resulted in a five- to sixfold up-regulation of promoter activity in uninduced MEL cells, but only three- to fourfold stimulation was observed from the mutant promoters during MEL cell terminal differentiation. This finding suggests that all three sites are required for repressor activity in uninduced MEL cells and that derepression occurs during MEL cell differentiation. BB1 DNA-binding activity decreases during MEL cell differentiation, suggesting a central role for this factor in modulating the effects of the repressor element. The BB1-binding factor also competes with the CCAAT-binding protein for binding the CCAAT motif. The fact that a reduced but significant stimulation of promoter activity during differentiation is observed in the absence of the repressor element raises the possibility that the BB1 factor also down-regulates transcription in undifferentiated MEL cells by displacing binding of CCAAT-binding protein to the proximal CCAAT motif.

Animals↗
PubMed1990

Regulation of erythroid-specific gene expression.

The aim of our group's work has been to elucidate how the alpha- and beta-globin genes come to be co-expressed together with a set of characteristic non-globin genes during erythroid cell differentiation. Our most significant progress concerns the identification and analysis of a species-conserved transcription factor, EF1, that appears to play a general role in the regulation of erythroid-specific gene transcription. We have shown that the 4 kb of 5' flanking region of the mouse alpha-globin gene contains two erythroid-specific cis-control elements, both of which involve EF1 binding sites. We have also identified functionally active EF1 binding sites in the mouse beta-globin promoter, as well as in the erythroid-specific promoter of the gene encoding the haem biosynthetic enzyme, porphobilinogen deaminase (PBG-D). The function of the PBG-D promoter depends in part on the cooperation between an EF1 binding site and an adjacent CACCC motif, this being abolished if their spacing is increased beyond 40 nt. We have also investigated the mechanisms involved in the up-regulation in erythroid cells of two non-globin genes we have cloned, encoding the RBC-specific lipoxygenase (LOX) and glutathione peroxidase (GSHPX). As judged by the presence of tissue-specific DNAse I hypersensitive sites, the tissue-specific regulation of the GSHPX gene seems to be due to regulatory regions 3' to the gene. The level of GSHPX is also regulated by selenium and this occurs at two levels: during mRNA formation, and during translation of the mRNA due to the regulation of selenocysteine incorporation specified by a unusual use of the UGA codon.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

GATAAG; a cis-control region binding an erythroid-specific nuclear factor with a role in globin and non-globin gene expression.

An erythroid-specific nuclear protein factor binds to a sequence motif (GATAAG) which is present in the promoter region of the mouse alpha and beta major globin genes, and in the erythroid-specific promoter of the human porphobilinogen deaminase (PBG-D) gene. The protein activity is conserved across species, being found in mouse erythroleukaemia (MEL) cells, chicken erythrocytes, the human erythroid K562 and KMOE cell lines, but not in a variety of non-erythroid mouse tissues or in HeLa cells. Functional analysis of this element in the alpha globin gene promoter by stable transfection experiments show that the GATAAG motif resides in a 68 bp sequence which has a stimulatory effect on transcription in mouse erythroleukaemia but not fibroblast cells. The GATAAG motif is conserved in the promoters and 3' enhancers of a variety of globin and non-globin genes implying that it is a cis-element involved in the tissue-specific up-regulation of several genes that are co-expressed during erythroid cell differentiation.

Animals↗
PubMed1988

cis and trans control of erythroid cell-specific gene expression during erythropoiesis.

The overall aim of our group's work is to investigate the molecular mechanisms regulating erythroid cell-specific gene expression during erythroid cell differentiation. We have been successful in cloning two non-globin genes of interest: the first encodes the rabbit red cell-specific lipoxygenase (LOX), which has a role in degrading mitochondrial lipids during maturation of the reticulocyte to the erythrocyte; and the second, mouse glutathione peroxidase (GSHPX), an important seleno-enzyme responsible for protection against peroxide-damage. Characterization of the GSHPX gene revealed that the seleno-cysteine residue in the active site of the enzyme is encoded by UGA, which usually functions as a translation-termination codon. This novel finding has important implications regarding the role of mRNA sequence context effects in codon recognition. In contrast with the beta-globin locus, very little is known about the mechanisms responsible for the erythroid-specific expression of the alpha-globin genes. By a combination of functional transfection assays and studies of the interactions of nuclear sequence-specific DNA-binding proteins with promoter sequences in vitro, we have recently defined two regions upstream of the mouse alpha-globin gene involved in its erythroid-specific expression: one contains a sequence motif (GATAAG) that binds to a species-conserved and erythroid-specific factor both in vitro and in vivo. Interestingly, GATAAG motifs binding the same factor are found also in the mouse and chicken adult beta-globin gene promoters, the erythroid-specific promoter of the haem pathway enzyme, porphobilinogen (PBG) deaminase and the chicken beta-globin 3' enhancer. We are now commencing purification of this erythroid-specific GATAAG-binding factor, investigating in more detail how it functions in relation to other globin gene control regions and determining whether GATAAG-like regions have a functional role in the erythroid-specific expression of other genes. We have begun to investigate the regulation of the GSHPX and red cell LOX genes. The presence of tissue-specific 3' DNAse I-hypersensitive sites (DHSS) suggests that different 3' flanking regions of the GSHPX gene may be important in its regulation in the various cell types in which it is highly expressed, i.e. erythroid cells, liver and kidney.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗